Sexual Behavior Determined by Immune Cells in the Brain

The immune system is not typically taken into consideration by neuroscientists when discussing sexual behavior in the developing brain. Yet now, a new study from investigators at The Ohio State University (OSU) may have many scientists rethinking behavioral development, as the researchers found a surprising new explanation of how young brains are shaped for sexual behavior later in life. Findings from the new study—published recently in the Journal of Neuroscience through an article titled “Mast Cells in the Developing Brain Determine Adult Sexual Behavior”—show that the immune cells appear to play an important role in determining whether an animal's sexual behavior will be more typical of a male or female.

To better understand the role of the mast cells in sexual behavior, the research team silenced the mast cells in male fetal rats and then observed the rats' development later in life. Subsequently, the altered rats were paired with a female that was receptive to mating and observed to determine whether the males sexually pursued the females.

Interestingly, the experimental males were far less interested in the female rats than typical males, acting almost like females. Moreover, the researchers also manipulated female newborn rats, activating the mast cells with a stimulating chemical. As adults, they acted like males.

“It's fascinating to watch because these masculine females don't have the hardware to engage in male reproductive behavior, but you wouldn't know it from the way they act,” notes lead study investigator Kathryn Lenz, Ph.D., an assistant professor of psychology and neuroscience at OSU. “They appear to be strongly motivated to try to engage in male sexual behavior with other females.”

In the current study, the OSU researchers found that estradiol, (which plays a significant role in the development of masculine traits in rats) activates mast cells in the brain and that those mast cells drive the animal's sexual development.

“Newborn male rats had greater numbers and more activated mast cells in the preoptic area (POA), a brain region essential for male copulatory behavior, than female littermates during the critical period for sexual differentiation,” the authors wrote. “Inhibiting mast cells with a stabilizing agent blunted the masculinization of both POA neuronal and microglial morphology and adult sexual behavior while activating mast cells in females, even though fewer in number, induced masculinization.”

Though scientists know that sex differences are programmed by hormones during early development, they have limited information about the cellular-level changes that contribute to the way the brain and behavior are formed.

“We're interested in the fundamental mechanisms that drive brain development and sex-specific brain development, and this study found that mast cells—immune cells involved in allergic responses—play a key role,” Dr. Lenz explains.

The researchers surmised that if human development mirrors what was seen in this animal study, it's possible that relatively minor influences—such as an allergic reaction, injury, or inflammation during pregnancy—could steer sexual behavior development in offspring. It's even conceivable that taking antihistamines or pain relievers during pregnancy could play a role. Furthermore, this discovery could help explain risks for psychiatric and neurological disorders that are more common in males, including autism.

“These mast cells in the brain appear crucial for life-long brain development, even though there are relatively few of them, and this should really open our eyes to the potential role of different immune cells in the human brain,” Dr. Lenz remarks. “There's so much we don't know, and we need to pay attention to all the cells in the brain and how they talk to each other.”

Previous work by the researchers uncovered the role of another type of brain cell, microglia, in directing sexual behavior. Amazingly, in the new study, they found that mast cells activate the microglia.

“This new mast cell discovery is one of those accidents of science,” D. Lenz states, explaining that another researcher was conducting some unrelated work on sex differences in gene expression and noticed that there appeared to be some differences in mast cell genes depending on whether the brains were from a male or female.

In addition to the behavioral changes documented in the study, the researchers examined cellular-level changes as well. Female newborn rats exposed to a dose of the masculinizing hormone estrogen had an increase in mast cells in the brain. Those cells released histamine, which stimulated other brain cells (the microglia) to activate male-typical brain patterning.